Anxiety disorders (ADs) in children are common and increasingly recognized as a major public health concern. In addition to the psychological suffering and disability associated with childhood ADs, anxiety during childhood is a significant risk factor for anxiety disorders, depression and substance abuse later in life. Despite the prevalence and impact of childhood anxiety, little is known about the brain alterations that mediate its development and pathophysiology. The overall aim of this proposal is to identify intermediate brain phenotypes that are linked to AD symptoms in young children (age 8-12). Using structural and functional magnetic resonance imaging, these studies will test the hypothesis that altered prefrontal-amygdala connectivity and exaggerated amygdala response during different phases of experiencing a mild social threat are associated with the symptoms of anxiety. While these methods have been commonly used in adults and less frequently in adolescents, very few neuroimaging studies have been conducted with preadolescent children with anxiety. A better understanding of anxiety symptoms as they develop may create opportunities for early diagnosis and intervention to reduce or even prevent future psychopathology. Understanding alterations in the neural circuitry that underlies the expression of ADs in preadolescent children will provide a rationale for using biomarkers aimed at early detection, as well as a developmental framework to understand the integrity of brain circuits associated with the earliest expressions of psychopathology. This knowledge may also set the stage for the development of psychosocial and pharmacologic interventions that target key components of the involved neural circuit and take into account the plasticity of the developing child's brain. Early, more effective interventions that are based on a sound neurodevelopmental rationale hold the promise for the prevention of later adolescent and adult anxiety, depression and substance abuse. These data will also lay the foundation for prospective longitudinal studies examining the utility of assessing amygdala function and prefrontal-amygdala connectivity for early detection and treatment of childhood anxiety. The proposed projects are of high scientific impact, and provide a unique opportunity for Dr. Williams to expand her training in psychiatric neuroimaging to include studies of pediatric anxiety patients and to learn functional and structural connectivity methods to evaluate the integrity of amygdala networks in childhood ADs. Dedicated clinical training will enhance Dr. Williams' experimental background, making her better equipped to conduct research with clinical applications. Data collected during the F32 period will be used for a planned R01 submission for a large, multi-site imaging study of childhood ADs, on which Dr. Williams will be a co-PI, and an independent K01 application. Working on this exciting translational project, taking a first- author role on resulting publicatios, and assuming a PI role on applications for extramural funding will facilitate Dr. Williams' transition to an independent research position.